Clinical Trial Summary

Cardiac computed tomography (CCT) is one of the standard non-invasive imaging techniques
allowing imaging of the heart and coronary arteries with a high temporal and spatial
resolution. The high sensitivity and negative predictive value (NPV) of coronary CT
angiography (CCTA) make it a valuable tool in the assessment of coronary artery disease (CAD)
in patients with low to intermediate risk for CAD, especially to rule out CAD. This risk
stratification can be done with help of multiple different risk-calculators (e.g. the updated
Diamond-Forrester model by Genders et al. 2012). These calculators take different variables
into account, e.g. advanced age, gender, blood pressure, diabetes mellitus (DM), lipid
profile and smoking.

Patients with cardiac diseases often have multiple risk factors for developing contrast
induced nephropathy (CIN), e.g. diabetes mellitus, advanced age, hypertension and chronic
kidney disease. Although the relationship between CTA and CIN has recently come to discussion
(AMACING trial; Nijssen et al. 2017), it is still desirable to minimise the CM volume used in
these patients. One method to reduce the CM volume is to personalise the injection protocols.
The personalisation of injection protocols to the individual patient is gaining more
attention in the field of CT imaging. The goal is to individualise the injection protocols to
a level, where the patient only receives the minimal amount of CM needed to acquire a
diagnostic scan, while maintaining a diagnostic image quality. Many techniques are available
and have been studied, e.g. adjustment of CM volume to scan protocol, CO, lean body weight
(LBW) and BW.

However, no data is available on which of these is the most beneficial method for the
personalisation of CM injection protocols. Therefore, the aim of this study is to assess the
performance of three different personalized injection protocols (based on CO, LBW and BW) in
CCTA with regard to image quality in comparison to previously used protocols in our
department. We hypothesize that the personalized injection protocols will be non-inferior,
provide a homogenous coronary enhancement (less non-diagnostic scans) in patients, and will
account for a reduction of CM volume in our department in comparison to the previously used
protocols.

Clinical Trial Description

Cardiac diseases still are the leading cause of death in the western world. Besides the high
mortality of the cardiac disease itself, recent studies have shown an increasing evidence of
the prognostic value of cardiac diseases, particularly coronary artery disease (CAD), in a
broad variety of other diseases. Especially in patients with oncological pathologies
undergoing radiotherapy or lung resection surgery [Ambrogi et al. 2003; Kanzaki et al. 2017;
Khakoo et al. 2008; Basacaraju et al. 2002; Fajardo et al. 1972]. Cardiac computed tomography
angiography (CCTA) is one of the standard non-invasive imaging techniques allowing imaging of
the heart and coronary arteries with a high temporal and spatial resolution. The high
sensitivity and negative predictive value (NPV) of CCTA make it a valuable tool in the
assessment of CAD. Especially to rule out CAD in patients with low to intermediate risk for
CAD [Hendel et al. 2006; Goldstein et al. 2011; Budoff et al. 2008; Meijboom et al. 2008;
Roffi et al. 2016].

The aim of CCTA is to achieve a high diagnostic accuracy, which depends on both optimal
intravascular enhancement (in Hounsfield Units (HU); minimal 325 HU) and contrast-to-noise
ratio (CNR). Optimal intravascular enhancement and CNR depend on multiple factors, such as
scan technique (e.g. tube voltage (kV) and tube potential), parameters of the administered
contrast material (CM) (e.g. concentration, flow rate) and patient related factors (e.g. body
weight (BW), heart rate or cardiac output [CO]) [Bae et al. 2004; Awai et al. 2004].
Dedicated CT protocols are necessary to image the heart and the coronary arteries. These
protocols require a correlation to the patient's electrocardiogram (ECG) in order to minimize
cardiac motion and deliver a sharp image of the heart and coronary arteries. Depending on the
heart rate of the patient, the scan can either be a prospectively ECG-triggered high-pitch or
adaptive sequence, or retrospectively ECG-gated helical scan.

The personalisation of injection protocols to the individual patient is gaining more
attention in CT imaging, and the goal is to individualise the injection protocols to a level,
where the patient only receives the minimal amount of CM needed to make a diagnostic scan
with a diagnostic image quality. Besides the techniques mentioned above, other techniques are
possible, e.g. adjustment according to patients CO, lean body weight (LBW), and BW.

Both blood volume and CO increase with an increasing BW. When CO increases, the distribution
of CM is also increased. On one hand this results in a fastened test bolus arrival, on the
other hand in a decreased and shortened intravascular attenuation profile (in comparison to a
decreased CO) [Bae KT 2010]. Therefore, both timing and CM volume can be adjusted to CO in
order to achieve a similar intravascular attenuation profile.

LBW is a measurement for body fat percentage. It is known that fatty tissue is not as well
vascularised in comparison to muscle tissue. Thus with increasing BW due to fatty tissue, the
blood volume does not increase linear to BW. For instance, patients with a high BW due to
increased muscle tissue, need more CM volume compared to patients with a high BW due to fatty
tissue. The concept of LBW accounts for this fact [Bae KT 2010].

When adjusting CM volume to BW, less CM volume is needed with a lower BW in comparison to a
higher BW, due to the decreased blood volume and CO [Bae KT 2010].

The tube voltage, set by automated tube voltage selection (ATVS, CAREkV, Siemens, Berlin,
Germany), needs to be taken into account as well. CAREkV is a software program which chooses
the optimal tube voltage (kV) and tube current (mAs) settings for the individual patient,
based on their topograms, while maintaining a diagnostic image quality. Lower kV settings
result in a higher intravascular enhancement if the same amount of CM is used, thus giving
the potential to decrease CM volume in lower kV settings.

Since no data exist on the optimal method of choice, the aim of this study is to assess the
performance of three personalized injection protocols (CO, LBW and BW) in CCTA, in comparison
to previously used protocols, with regard to image quality. Secondly we want to assess the
presence and severity of CAD in patients undergoing CCTA with help of the coronary artery
disease reporting and data system (CAD-RADS).

A total of 330 patients will be included in this prospectively observer blinded randomized
controlled non-inferiority trial. All patients will be randomised in one of three groups (CO,
LBW and BW) with help of a randomisation software program (ALEA). The control group will
consist of 110 consecutive patients who will be included retrospectively.

Interventional studies are often prospective and are specifically tailored to evaluate direct impacts of treatment or preventive measures on disease.

Observational studies are often retrospective and are used to assess potential causation in exposure-outcome relationships and therefore influence preventive methods.

Expanded access is a means by which manufacturers make investigational new drugs available, under certain circumstances, to treat a patient(s) with a serious disease or condition who cannot participate in a controlled clinical trial.

Clinical trials are conducted in a series of steps, called phases - each phase is designed to answer a separate research question.

Phase 1: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

Phase 2: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.

Phase 3: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

Phase 4: Studies are done after the drug or treatment has been marketed to gather information on the drug's effect in various populations and any side effects associated with long-term use.

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